Molecular and clinical profiling of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs): An analysis of the Oncology Research Information Exchange Network database.

Abstract

669 Background: The incidence of neuroendocrine tumors (NETs) is approximately 7 per 100,000 persons and rising. By location, tumors in the gastroenteropancreatic (GEP) region, particularly midgut NETs, are most common. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling, providing opportunities to identify novel associations between molecular features and clinical outcomes in GEP-NETs. Methods: Survival analyses were performed using the log-rank testing, and clinical features were evaluated using Wilcoxon and chi-squared tests. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test. Transcriptomic analyses utilized a student’s t-test. We reviewed 240 samples from 226 patients, with 124 of pancreatic origin, 90 small bowel, 16 gastric, and 10 colorectal. All specimens were well-differentiated; further grading information was unavailable on the ORIEN platform. A p-value <0.05 was considered significant. Results: Patients with metastatic disease were significantly younger at diagnosis (58 vs. 61 years, p=0.0242) and had significantly higher tumor mutational burden (TMB) (0.48 vs. 0.32 mut/Mb, p=0.001). Among the 100 most common alterations across the entire cohort, BPTF (p=0.03) and PRKCA (p=0.007) mutations were more prevalent in pancreatic NETs than in other primary sites. The most frequently mutated genes identified included TTN (27.7%), MUC16 (25.1%), CCDC168 (22.1%), KIR3DL1 (20%), TGIF2LX (20%), MUC17 (19.1%). TTN mutation was significantly associated with higher TMB (p<0.0001). The most common copy number alteration was MUC3a amplification (7q22.1) in 61.5% of samples. This amplification was associated with more prolonged overall survival (OS) with a significance of p=0.0501. Patients with NETs harboring a mutation in CSNK2A2 (p=0.0149), WDR74 (p=0.0386), or NCMAP (p=0.0248) experienced significantly shorter OS compared to the cohort as a whole. Conclusions: We report the first clinical, genomic, and transcriptomic analysis of ORIEN GEP-NET cases. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of well-differentiated NETs. Most prevalent mutations in GEP-NETs from ORIEN database. Mutation Prevalence (Percentage of Samples) TTN 27.7% MUC16 25.1% CCDC168 22.1% KIR3DL1 20.0% TGIF2LX 20.0% MUC17 19.1%